Clinics in Dermatology (2014) 32, 364–375

Autoimmune blistering dermatoses as systemic diseases Snejina Vassileva, MD, PhD ⁎, Kossara Drenovska, MD, PhD, Karen Manuelyan, MD Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, 1 Georgi Sofiiski Boulevard, 1431 Sofia, Bulgaria

Abstract Autoimmune blistering dermatoses are examples of skin-specific autoimmune disorders that can sometimes represent the cutaneous manifestation of a multiorgan disease due to potential common pathogenic mechanisms. As soon as a distinct autoimmune blistering dermatosis is diagnosed, it is imperative to consider its potential systemic involvement, as well as the autoimmune and inflammatory conditions that are frequently associated with it. In paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, the internal organs (particularly the lungs) are affected by the autoimmune injury. Pemphigus erythematosus may manifest with overlapping serologic and immunohistologic features of lupus erythematosus. In patients with bullous pemphigoid, there is a greater prevalence of neurologic disease, possibly caused by cross-reactivity of the autoantibodies with isoforms of bullous pemphigoid antigens expressed in the skin and brain. Anti-laminin 332 pemphigoid shows an increased risk for adenocarcinomas. Patients with anti-p200 pemphigoid often suffer from psoriasis. A rare form of pemphigoid with antibodies against the α5 chain of type IV collagen is characterized by underlying nephropathia. Particularly interesting is the association of linear IgA disease or epidermolysis bullosa acquisita with inflammatory bowel disease. Dermatitis herpetiformis is currently regarded as the skin manifestation of gluten sensitivity. Bullous systemic lupus erythematosus is part of the clinical spectrum of systemic lupus erythematosus, a prototypic autoimmune disease with multisystem involvement. © 2014 Elsevier Inc. All rights reserved.

Introduction Autoimmune blistering dermatoses (AIBDs) represent a heterogeneous group of rare organ-specific autoimmune diseases characterized by blistering of the skin and mucous membranes. They are associated with tissue-bound and circulating autoantibodies to structural components of the skin. AIBDs are divided into two main categories depending on whether the cleavage plane is intraepidermal, as in pemphigus, or at the basement membrane zone (BMZ), as in the group of subepidermal blistering diseases. These disorders, particularly the pemphigus group, are important for the morbidity associated with the involvement of skin and mucous membranes, especially if left untreated. Rupture of blisters leads to painful erosions that cause significant loss of fluid, electrolytes, and proteins, mainly in cases of extensive ⁎ Corresponding author. Tel.: +359 2 9230379; fax: +359 2 8518779. E-mail address: [email protected] (S. Vassileva). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.003

body surface involvement. If the oral mucosa, pharynx, and esophagus are involved, the patient may not be able to tolerate adequate intake of food and medication. These changes lead to immunosuppression, which along with the lack of epidermis secondary to erosions predispose patients to life-threatening infections and sepsis. Although the primary problem in AIBDs is in the skin and/or mucous membranes, they are associated with secondary systemic complications that may be potentially fatal. Immunobullous diseases provide another challenge, because their treatment warrants the use of high doses of systemic corticosteroids and immunosuppressive drugs associated with various adverse side effects and high risk for serious systemic complications. The latter have been extensively discussed in the literature and will not be considered in this review. It has been well documented that both organ-specific and systemic autoimmune diseases may coexist in the same patient, either sequentially or concurrently, sustained by the presence of autoantibodies directed against the corresponding

AIBDs as systemic diseases

365 autoantigens. This is illustrated by the association of the organ-specific AIBDs with other organ-specific or systemic autoimmune disorders. Multiple factors, including those of immunologic, genetic, endocrine, and environmental origin, contribute to this coexistence.1 In addition, several reports have focused on the association of bullous dermatoses with many differing internal conditions. Most of these associations have been already reviewed previously.2,3 There is a growing body of evidence, however, that some of the bullous disorders may represent the cutaneous manifestation of a multiorgan disease because of potential common pathogenic mechanisms. In this contribution, the AIBDs that warrant further investigation for occult underlying systemic disease will be discussed. Table 1 summarizes blistering diseases and their well-documented systemic associations.

Table 1 Autoimmune blistering diseases with potential systemic involvement Disease

Potential systemic involvement

Pemphigus erythematosus Endemic pemphigus (Columbia) Paraneoplastic pemphigus Bullous pemphigoid Anti-laminin 332 pemphigoid Anti-p200 (laminin γ1) pemphigoid α5 chain of type IV collagen blistering disease Pemphigoid gestationis

Systemic lupus erythematosus Systemic lupus erythematosus

Linear IgA dermatosis Dermatitis herpetiformis Epidermolysis bullosa acquisita Bullous systemic lupus erythematosus

Table 2

Hematologic malignancies Neurologic diseases Adenocarcinoma Psoriasis Nephropathy Pregnancy or trophoblastic tumors Inflammatory bowel disease Celiac disease Inflammatory bowel disease (Crohn’s disease) Systemic lupus erythematosus

Pemphigus Pemphigus is a group of rare autoimmune blistering diseases, characterized by the occurrence of autoantibodies against desmosomal structure proteins (Table 2). Deposition

Target antigens and immunofluorescence findings in pemphigus

Diagnosis

Autoantigen

DIF

IIF

Pemphigus vulgaris

Dsg 3, Dsg 1 (Dsg 4) Acetylcholine receptor Dsc 1-3 Dsg 3 Dsg 1 Dsc 3 Dsg 1 (Dsg 4) Plakoglobin

Intercellular IgG and C3 in the epidermis/epithelium

Intercellular IgG antibodies on monkey esophagus

See pemphigus vulgaris

See pemphigus vulgaris

Intercellular IgG and C3 in the epidermis

Intercellular IgG antibodies on monkey esophagus or guinea pig lip/tongue Intercellular IgG antibodies on monkey esophagus; ANA on monkey esophagus or Hep-2 Intercellular IgG antibodies on monkey esophagus

Pemphigus vegetans

PF

PE

Endemic pemphigus

Dsg 1

Northern Colombia Pemphigus herpetiformis

Dsg 1 (Dsg 3)

Paraneoplastic pemphigus

Drug-induced pemphigus

IgA pemphigus

Dsg 3, Dsg 1 Desmoplakin 1 and 2 Envoplakin, Periplakin, A2ML1 (170-kDa protein) Plektin, Dsc 1–3, BP230 Dsg 1 (Dsg 3)

Dsg 3 Dsg 1 Dsc 1 (IgA)

Intercellular IgG and C3 in the epidermis; lupus band (IgG and C3) at the BMZ See PF See PE Intercellular IgG and C3 in the epidermis Intercellular IgG and C3 in the epidermis; linear IgG and/or C3 along the DEJ Intercellular IgG and C3 in the epidermis; sometimes linear IgG or C3 Intercellular IgA and C3 in the epidermis

Intercellular IgG antibodies on monkey esophagus Intercellular IgG antibodies on monkey esophagus and on plakin rich substrate (rat urinary bladder)

Intercellular IgG antibodies on monkey esophagus Intercellular IgA antibodies on monkey esophagus

A2ML1, α2 macroglobulin-like 1; ANA, antinuclear antibodies; BMZ, basement membrane zone; BP, bullous pemphigoid; DEJ, dermal–epidermal junction; DIF, direct immunofluorescence; Dsc, desmocollin; Dsg, desmoglein; IIF, indirect immunofluorescence; PE, pemphigus erythematosus; PF, pemphigus foliaceus.

366 of autoantibodies to their target antigens causes loss of cell– cell adhesion between keratinocytes and intraepithelial blister formation called acantholysis. Pemphigus is classically divided into two main subtypes, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), that differ in their clinical, histologic, and immunologic features and prognosis. A third subtype of the disease, paraneoplastic pemphigus (PNP), was described in 1990 as atypical pemphigus, occurring in patients with associated neoplasia, most commonly of lymphoproliferative origin.4 Besides, several other subtypes of pemphigus exist, including pemphigus vegetans, pemphigus erythematosus (PE), endemic PF, pemphigus herpetiformis, drug-induced pemphigus, and IgA pemphigus. The diagnosis in all these variants is confirmed by histology, direct (DIF) and indirect immunofluorescence (IIF) microscopy, and immune serology (Table 2). Classic pemphigus variants, such as PV and PF, are believed not to affect internal organs and other body systems. At the same time, pemphigus often demonstrates a severe clinical course, physical impairment, significant impact on the quality of life (QOL), and life-threatening potential. All these negative characteristics of the disease are likely to be related to other, more complex mechanisms besides isolated skin and mucous membrane involvement. In the literature, there are innumerable reports on the associations of pemphigus with other autoimmune, inflammatory, or neoplastic disorders, affecting the organism in its integrity.5 Being itself an autoimmune disorder, pemphigus is very likely to be associated with other disturbances of autoimmune nature, both organ-specific and systemic ones. The tendency to develop another disease occurs in about 25% of the patients.6 Inflammatory and infectious conditions, malignancies, endocrinopathies, and hormonal changes during pregnancy, food and drug intake, smoking, exposure to trauma, radiation, or pesticides may all be related to triggering or exacerbation of pemphigus. This is the reason for many authors to regard such cutaneous disorders as pemphigus, psoriasis, or urticaria as systemic ones. PNP is the only form of pemphigus in which internal organs can be affected by autoimmune injury. PNP is mostly associated with lymphoproliferative neoplasms, such as, non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, and less commonly thymoma and retroperitoneal sarcomas.7 Patients with PNP present with painful mucosal erosions that appear erythema multiformelike or Stevens-Johnson-like (Figure 1A), and polymorphic skin lesions showing a wide variation in morphology. Since its original description, the spectrum of PNP subsequently expanded to include many clinical forms, including lichenoid eruptions,8 which may not necessarily comprise bullae, erosions, or both.9 There has also been growing evidence of involvement of internal organs, such as lungs, thyroid, kidney, smooth muscles, and gastrointestinal tract.10 The constellation of clinical, histopathologic, and immunologic features has prompted several revisions of the diagnostic criteria for this subtype of pemphigus.11–13

S. Vassileva et al.

Fig. 1 A, Severe mucositis in a patient with paraneoplastic pemphigus and B-cell lymphoma. B, Periungual blistering lesions in the same patient with paraneoplastic pemphigus.

The additional recognition of systemic involvement and clinical heterogeneity in PNP resulted in its broader classification under the heading of paraneoplastic autoimmune multiorgan syndrome (PAMS).14 This term has been adopted as more appropriate to encompass the full spectrum of signs and symptoms associated with this challenging paraneoplastic process. In addition, some authors have suggested that the former term PNP describes only the classic epithelial manifestations of PNP/PAMS, and it may lead to overlooking the multiorgan nature of this syndrome in cases presenting without blistering lesions.15 PNP/PAMS fundamentally differs from classic pemphigus variants in several ways. It is a rare disease with approximately 450 patients reported in the literature to date.15 Most cases occur between 45 and 70 years of age, but children and adolescents may also be affected.16 Men are more frequently involved than women,17 in contrast with PV, which shows a female predominance.18 An association of PNP with HLA class II DRB1*03 allele has been reported in contrast with PV that is associated with HLA-DRB1*14 and -DRB1*04:02.19 A key distinction between clinical features of PNP/PAMS and classic pemphigus is that PNP/PAMS may present with inflammatory skin lesions over the trunk and extremities. Lesions in PNP/PAMS often arise on the palms and soles, and in the periungual areas (Figure 1B), which is not a common location for the blisters in PV. Nikolsky sign is positive in PV,

AIBDs as systemic diseases but negative in PNP/PAMS. The latter is characterized by a diffuse intractable stomatitis, whereas in PV, mucosal erosions are usually more discrete and isolated. Cicatrizing conjunctivitis is particularly common in PAMS but is not observed in PV. PAMS can manifest with several clinical phenotypes (at least five): Pemphigus-like, bullous pemphigoid (BP)-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like. Pemphigus vegetans-like,20 psoriasiform, and pustular forms21 have been additionally described. Autoantibodies can be directed against an antigen complex comprising all the plakin family members (Table 2). In addition to the humoral response, the pathophysiology of PNP/ PAMS also incorporates a cellular autoimmunity response, mediated by CD8+ cytotoxic T lymphocytes, CD56+ natural killer cells, and CD68+ monocytes and macrophages.15 PV rarely, if ever, affects other organs, except for the esophageal mucous membranes, whereas PNP/PAMS commonly affects the respiratory mucous membranes.15 Rapidly progressive respiratory failure, caused by pulmonary involvement, constitutes the terminal event in approximately 30% of these patients. This complication first manifests itself as obstructive disease affecting both large and small airways. It is due to deposition of PAMS autoantibodies in bronchial epithelia that leads to dyskeratosis and acantholysis of bronchial epithelial cells that detach from the lamina propria and neighboring cells. The lumen of the affected bronchioles becomes severely stenotic, and patients develop a functional pattern of obstructive or restrictive bronchiolitis. As a result, autoantibody-mediated injury takes an important role in the pathogenesis of bronchiolitis obliterans in PNP/PAMS, and is the cause of rapidly progressive and often fatal respiratory failure. Histologic study of a lung biopsy will demonstrate dense lymphohistiocytic infiltration, as well as fibrosis around bronchioles. Patients have a dry cough and severe dyspnea, associated with decreased blood pO2. Chest radiography and computed tomography are often negative. With pulmonary function testing, however, marked obstructive patterns with limitation in diffusion capacity are diagnostic.21 Pulmonary injury has appeared to account for the very high mortality rates observed among children and adolescent patients (10/14 patients in the largest reported series).16 The results of a multicenter study recently carried out in France showed that the presence of erythema multiforme-like skin lesions in association with histologic keratinocyte necrosis is a poor prognostic factor in patients with PNP who are likely to have a more severe and rapid fatal outcome, and should be managed very carefully.22 PNP/PAMS is traditionally difficult to treat. Often patients are resistant to all conventional therapies. Prednisone, combined with immunosuppressive agents, including immunoablative cyclophosphamide, cyclosporine A, plasmapheresis, immunoapheresis, rituximab, and, most recently, alemtuzumab are recommended.15 Early detection and complete resection of the tumor are of paramount importance and prerequisites for a better outcome.21 Prognosis depends on the nature of the underlying malignancy and the

367 development of severe respiratory failure. The distinction of PNP/PAMS from the other subtypes of pemphigus is of critical importance, because PAMS has a poor prognosis and is rapidly fatal. Unfortunately, because the inciting malignancy and the paraneoplastic syndrome do not always follow the same evolution, patients with PNP/PAMS may often progress to recalcitrant mucosal or pulmonary disease even in cases when the malignancy has been treated and is in remission. Another variant of pemphigus that may display systemic involvement is PE, also known as Senear–Usher syndrome. It was initially described nearly a century ago by Francis Senear and Barney Usher in Chicago in 11 patients with pemphigus who shared clinical features of lupus erythematosus (LE) and whose biopsies revealed acantholysis.23 PE is currently recognized as a variant of PF with overlapping clinical, serologic, and immunohistologic features of LE.24 PE clinically presents with erythematous, scaly, and superficially eroded lesions with a seborrheic distribution. The involvement of sun-exposed areas, namely, the face, scalp, and upper part of the chest and back, suggests induction of the lesions by sunlight. On the face, the skin changes often exhibit the “butterfly” distribution of LE. PE shares common histopathology and immunofluorescence findings with PF.25 They differ in that PE typically has positive circulating antinuclear antibodies and a positive lesional lupus band test in addition to intercellular staining on DIF. When tested by IIF on epithelial cell substrate, serum samples from patients with PE produce the typical pemphigus network epithelial cell-surface fluorescence, often combined with staining of the keratinocyte nuclei (Figure 2). Patients with PE may also have other signs of systemic involvement, such as anemia, lymphopenia, thrombocytopenia, renal abnormalities, proteinuria, or positive rheumatoid factor. In addition to an association with LE, the concurrence of PE and myasthenia gravis has been described.24 Most of these patients had a thymoma and presented with antibodies to the cross striations of skeletal muscle in addition to immunologic evidence of pemphigus and LE. A variety of other immunologic diseases may be seen in patients with PE, a phenomenon that justifies considering this form of pemphigus as a distinct variant of the disease.26 Interestingly, PE was the predominant clinical phenotype among the patients in a recently described outbreak of endemic PF in Northern Colombia.27 Colombian cases of endemic pemphigus differ from those in other endemic foci, such as Brazil (Brazilian PF, fogo selvagem) and other South America countries.28 It differs from nonendemic forms in its geographic distribution, high familial incidence, younger age of onset, and poor general state.29 Clinically, most of the patients with Colombian endemic pemphigus showed keratotic follicular skin lesions resembling discoid LE, with a high degree of photosensitivity as in Senear–Usher syndrome, along with a lupus band-like deposition of immunoglobulins and complement at the BMZ. In addition, some hospitalized

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Fig. 2 Indirect immunofluorescence findings in pemphigus erythematosus: combined intercellular and nuclear staining on human esophagus substrate.

patients had proteinuria, hypoalbuminemia, generalized edema, hematuria, leukocyturia, and a frank nephrotic syndrome indicating possible renal failure. Pemphigus is a chronic disease with a sometimes severe clinical picture, relapses, and prolonged immunosuppressive treatment that impairs both physical and psychosocial aspects of QOL. There is a growing interest in QOL of such patients, and recent studies have demonstrated that QOL was worse in patients with nasal and pharynx involvement, positive Nikolsky sign, and severe skin lesions with intensive pruritus.30 PV was found to be responsible for great alteration in QOL, especially in its severe forms. High probability of anxiety and depression in patients with PV was also observed.31 These data lead to the conclusion that the management of pemphigus patients should take into account both their physical and their emotional condition at the start of the treatment.32

Pemphigoid group The pemphigoid group of AIBDs is characterized by the production of autoantibodies that target adhesion molecules which are part of the hemidesmosomes at the dermal– epidermal junction (DEJ). Their immunohistologic hallmark is the formation of a subepidermal blister and deposits of immunoreactants, usually IgG and complement, at the DEJ.

Bullous pemphigoid Bullous pemphigoid (BP) is the most common autoimmune blistering disease in Western European countries, typically affecting elderly individuals older than 60 years. Clinically, BP is characterized by a polymorphic eruption

S. Vassileva et al. consisting of large, tense blisters on inflamed or normalappearing skin, and urticaria-like and eczematous papules and plaques. BP is a prototypical organ-specific disease, mediated by antibodies against structural components of the cutaneous BMZ, namely, a 230-kDa protein called BP antigen 1 (BPAG1) and a 180-kDa transmembrane protein known as BPAG2 (Table 3). The pathogenic role of anti-BPAG2 antibodies has been widely accepted, and their serum levels have been found to parallel disease activity in patients with BP. The role of anti-BPAG1 antibodies in the pathogenesis of BP remains controversial, but their examination may be useful in a limited number of patients with BP and mucosal lesions or with negative anti-BPAG2 antibodies.33 Because target antigens are located within the cutaneous BMZ structures, other organs and systems are believed not to be primarily affected by the autoimmune process in BP. Over the past decade, however, there has been growing evidence of a higher prevalence of neurologic diseases in patients with BP, possibly caused by cross-reactivity between the BP180 and BP230 isoforms expressed in the skin and brain. The reported associations include not only dementia, cerebrovascular disease, or multiple sclerosis, but also Parkinson disease, gonadotropic adenoma, trembling, dyskinesia, and lumbar spinal stenosis.34 A significant increase in the odds of development of BP has been found in people with neurologic diseases.35,36 Dementia, Parkinson disease, and unipolar or bipolar disorder are independent risk factors for BP.37 An English study of 90 consecutive patients with BP and 141 control subjects showed that patients with BP had greater than 6-fold increased odds of any neurologic disease and a nearly 8-fold increased likelihood of dementia.38 In 72% of the patients with known onset of neurologic disease, BP developed later and was diagnosed after a median of 5.5 years. Common autoimmune mechanisms may be involved, as isoforms of BPAG1 (BP230) are expressed in the central and peripheral nervous systems.39 It has been shown that serum of patients who have both BP and neurologic disease recognizes BPAG1 in the human brain. In a study from China, a 230-kDa protein of human epidermal extract and a 230-kDa protein of human brain extract were recognized by serum samples from elderly patients with BP and concomitant neurologic disease in а significantly higher percentage compared with serum samples from patients with BP only, neurologic disease only, or control subjects.40 The authors conclude that both human skin and brain contain immunogenic BPAG1 in patients with BP and neurologic disease. The pathologic changes in elderly patients with neurologic disorders could expose the neural isoforms of BPAG1 or other BP antigens. In certain cases, autoantibodies, initially directed against neuronal isoforms of BP230, may cross-react with isoforms in the skin, causing the delayed development of BP after the onset of the neurologic symptoms.38 It has been speculated that neuroautoimmunity associated with the aging process or neurologic disorder may be involved in pemphigoid

AIBDs as systemic diseases Table 3

369

Target antigens and immunofluorescence findings in acquired subepidermal bullous diseases

Disease

Target antigens

Bullous pemphigoid

Ultrastructural location

DIF

IIF/split skin substrate

BP180 NC16A BP230 LAD-1 Mucous membrane pemphigoid BP180 NC16A, BP230, α6β4 Laminin 311 Anti-laminin 332 (antiepiligrin) Laminin 332 pemphigoid Anti-p200/Laminin γ1 Laminin γ1 pemphigoid α5 chain of type IV collagen α5(IV)NC1 blistering disease

Hemidesmosomes Linear deposits of IgG and/or C3 at the BMZ

Circulating IgG anti-BMZ antibodies—epidermal pattern

Lamina lucida

Linear deposits of IgG and C3 at the BMZ

Lower lamina lucida Lower lamina lucida Lamina densa

Linear deposits of IgG and C3 at the BMZ Linear deposits of IgG and C3 at the BMZ Linear deposits of IgG and C3 at the skin BMZ

Linear IgA bullous dermatosis

Lamina lucida

Linear deposits of IgA and C3 at the BMZ (rarely IgG or IgM) Linear deposits of IgG and C3 at the BMZ, rarely IgA and IgM Linear or granular deposits of IgG and C3 at the BMZ; rarely IgA and IgM Granular deposits of IgA and C3 along the BMZ, more intensive at the tips of the dermal papillae

Circulating IgG anti-BMZ antibodies—epidermal or mixed pattern Circulating IgG anti-BMZ antibodies—dermal pattern Circulating IgG anti-BMZ antibodies—dermal pattern Circulating IgG anti-BMZ (and anti-GBM) antibodies—dermal pattern Circulating IgA anti-BMZ antibodies—epidermal, dermal, or mixed pattern Circulating IgG anti-BMZ antibodies—dermal pattern

LAD-1 Type VII collagen

Epidermolysis bullosa acquisita Type VII collagen

Anchoring fibrils

Bullous systemic lupus erythematosus

Type VII collagen

Anchoring fibrils

Dermatitis herpetiformis

Epidermal transglutaminase

Papillary dermis

Circulating IgA anti-BMZ antibodies—epidermal, dermal, or mixed pattern IgA anti-endomysial antibodies on monkey esophagus substrate

α5(IV), α5 chain of type IV collagen; BMZ, basement membrane zone; DIF, direct immunofluorescence; GBM, glomerular basement membrane; IIF, indirect immunofluorescence; LAD, linear IgA dermatosis.

development via autoimmune response against dystonin, a cytoplasmic protein present in different compartments of a mature neuron (dendrites, axon, cell body) that shares homology with BPAG1.35 The homologous region of BPAG1 is the one recognized by autoantibodies in BP, which suggests that BP may be a marker of neuroimmune response and neurodegeneration. From a different perspective, circulating antibodies against epithelial isoforms of BP230 may recognize common sequences in neural isoforms and contribute to the neurologic manifestations. Causal associations, including age-related risk factors, immobility, and factors related to the management of the neurologic disease, have also been discussed.36 Historically, BP has been thought to have a better prognosis than pemphigus.41 Over the past decade several large European studies have demonstrated that even with treatment, patients with BP have a prognosis as grim as a diagnosis of end-stage heart disease, with more than 40% of patients dying within 12 months.42–44 Much of the mortality may be related to the age and the general condition of patients or secondary to treatment with corticosteroids and other immunosuppressive agents. In a retrospective study from Scotland, 48% of patients with BP died within 2 years of diagnosis, particularly from respiratory diseases.45 For

this reason, there is now a tendency to treat patients with less aggressive regimens. It has been suggested that patients with circulating antibodies to BPAG2 tend to have a poorer prognosis because of a more severe disease requiring higher doses of systemic steroids.46,47 BP has also been found in association with certain dermatoses, such as psoriasis and lichen planus. The inflammatory process near and within the DEJ, sometimes in combination with irritating therapy, for instance, tar or ultraviolet therapy, can lead to exposure of previously “hidden” antigens and subsequent autoimmune response. After the initial tissue damage, additional antigen epitopes may be targeted by antibodies in a process called epitope spreading, which is hypothesized to play a role in disease progression and chronicity,48 and cause development from one unrelated immunologic disorder to another.49 The coexistence of lichen planus and BP is referred to as lichen planus pemphigoides. Fortuitous associations of BP with various autoimmune, endocrine, and inflammatory disorders have been subject to isolated case reports or small series.5 In some cases, BP has been thought to be induced by physical injury (burn, radiotherapy, ultraviolet irradiation),50 or by numerous systemic or topical medications, or both.51

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Mucous membrane pemphigoid Mucous membrane pemphigoid (MMP), previously known as cicatricial pemphigoid, is a rare but well-defined variant of pemphigoid, characterized by erosive, scarring, subepidermal blistering lesions of mucosal surfaces, particularly of the oral and ocular mucosa (Figure 3), and less often, the skin. Depending on the mucosal surface that is mainly affected, patients with MMP may first present to the ophthalmologist, dermatologist, dentist, gastroenterologist, gynecologist, otolaryngologist, or primary care physician. Even though MMP is not a systemic disease by definition, mucosal involvement may interfere with the function of the digestive, respiratory, and reproductive systems, as well as disrupt normal vision and speech. The oral mucosa is almost always affected, followed by other mucosae (ocular, nasal, pharyngeal, laryngeal, esophageal, genital, and anal) and rarely the skin. Bullae quickly rupture, leaving slowly healing erosions, followed by scarring and adhesions between the various structures of the oral cavity. Laryngeal involvement may lead to a sore throat, hoarseness, and possible loss of speech. Supraglottic stenosis secondary to erosions, scarring, and edema may necessitate a tracheostomy, as the airway is further compromised. Esophageal erosions and scarring may result in the formation of strictures, with dysphagia, odynophagia, and weight loss. Ocular cicatricial pemphigoid is characterized by progressive subconjunctival cicatrization that leads to decreased vision, photosensitivity, scarring, and fibrosis that can eventually cause blindness. A rare variant of MMP with antibodies against laminin 332 is known as anti-laminin MMP (previously called antiepiligrin or anti-laminin 5 pemphigoid). It constitutes between 5% and 20% of all cases of MMP and is clinically indistinguishable from other forms of cicatricial pemphigoid.52 Anti-laminin MMP is associated with an increased relative risk for solid cancer, compared with the general population and similar to that for adults with dermatomyositis.53 Most patients have adenocarcinomas involving the gastrointestinal, gynecologic, and pulmonary systems, but non-Hodgkin and cutaneous T-cell lymphomas have been

Fig. 3 Mucous membrane pemphigoid: eye involvement with scarring.

S. Vassileva et al. also associated. Laminin-332 is essential for epithelial cell adhesion to the basement membrane but is also highly expressed in different cancer cells, promoting tumor growth, metastatic behavior, and invasion.54 Malignant tumors may show an aberrant synthesis of laminin-332, with subsequent induction of a secondary autoimmune response.55,56

Pemphigoid gestationis Pemphigoid gestationis (PG), previously known as “herpes gestationis,” is a rare pregnancy-specific form of pemphigoid. PG usually develops in the second or third trimester and clinically presents with severely pruritic urticarial lesions that progress to large tense bullae (Figure 4). The placenta has been suggested as the initiating organ, because the disease is not only associated with pregnancy, but also with hydatiform mole and choriocarcinoma,57 which should be considered in cases of persistence of PG for several months or onset of the disease more than 2 weeks after delivery. Blistering and early PG onset (first or second trimester) may lead to adverse pregnancy outcomes, including decreased gestational age at delivery, preterm birth, and low-birth-weight infants. Such pregnancies should be considered high risk and appropriate obstetric care should be provided.58

Anti-p200 (laminin γ1) pemphigoid Anti-p200 pemphigoid is a new subepidermal AIBD first described in 1996.59 It is characterized by circulating

Fig. 4 Pemphigoid gestationis: urticarial lesions and grouped vesicles on erythematous basis in the periumbilical area.

AIBDs as systemic diseases autoantibodies that bind to the dermal side of NaClseparated human skin and recognize a 200-kDa protein of the DEJ that was recently identified as the laminin γ1 chain.60 Although laminin γ1 is widely expressed in different basement mebranes, anti-laminin γ1 autoantibodies from patients with anti-p200 pemphigoid are associated only with skin blisters and show no pathology in other organs; however, patients with anti-p200 pemphigoid are often suffering from preexisting psoriasis. They tend to be of younger age than those with BP and present with a pruritic vesiculobullous eruption, mimicking BP. Rarely, dermatitis herpetiformis-like grouped papulovesicles and oral mucosal lesions can be observed.61 Several lines have suggested that expression of integrins is modified in the BMZ of psoriatic skin. Changes in integrin expression in basal keratinocytes may affect the laminin– integrin interaction, as well as the molecular kinetics and metabolism of laminins in the BMZ. These changes may be involved in anti-laminin autoantibody production. Pathogenic interaction between anti-laminin γ1 pemphigoid and psoriasis, which is currently recognized as a systemic disease, should be further elucidated.

A novel disease with autoantibodies against the α5 chain of type IV collagen In addition to the subepidermal AIBDs listed earlier, few patients have been described with a pemphigoid disease, characterized by renal insufficiency and autoantibodies against the α5 chain of type IV collagen [α5(IV) chain] of lamina densa. 62,63 α5(IV) chain is present at the DEJ, as well as in the glomerular basement membrane. Patients respectively suffered from a blistering skin eruption and nephropathy leading progressively to uremia. Kidney biopsy was consistent with crescentic glomerulonephritis, whereas skin perilesional biopsy revealed a subepidermal blister with marked polymorphonuclear infiltrate. In vivo deposited and circulating IgA and IgG antibodies reacting with the skin BMZ and the glomerular basement membrane were found on immunofluorescence testing (Table 3).63 This is in contrast with BP, linear IgA disease, and epidermolysis bullosa acquisita (EBA) autoantibodies that fail to react with the glomerular basement membrane. Despite the small number of patients with this novel blistering disease reported, it is of great interest because it represents the second primary human disease caused by autoimmunity to type IV collagen along with Goodpasture syndrome. The latter, however, is mediated by IgG antibodies to α3 chain of type IV collagen chain, which is present only in the renal glomerular basement membrane. This novel disease expands the repertoire of AIBDs and provides an explanation for the association of anti-type IV collagen autoantibodies and glomerulonephritis with subepidermal blisters.

371

Linear IgA dermatosis Linear IgA dermatosis (LAD) is a rare chronic autoimmune bullous disease associated with IgA anti-BMZ antibodies. Although LAD was historically confused with DH, it is now well recognized that these two IgA-mediated diseases are distinct entities. In contrast to DH, LAD shows no association with gluten-sensitive enteropathy, and the gluten-free diet is ineffective. LAD is mediated by IgA autoantibodies directed against heterogeneous antigen targets in the cutaneous BMZ (Table 3), which ultrastructurally localize to lamina lucida, anchoring fibrils, or lamina densa.64 LAD can occur at any age, but there are two peaks of onset: in adult individuals usually at 40 to 60 years of age and in children of preschool age. Most case series show a slight female predominance. 65 Improvement of LAD during pregnancy has been reported and reducing or stopping the medication if possible during pregnancy has been recommended, although postpartum relapses are likely.66 The clinical features of LAD can be heterogeneous. The cutaneous eruption is polymorphic and consists of pruritic urticarial papules, plaques, tense vesicles, and blisters, often in annular and polycyclic arrangement, appearing on the buttocks and perineum, as well as on the trunk and extremities. The annular pattern of the lesions is characteristically described as the “string of pearls” sign or “cluster of jewels” sign. Lesions are usually generalized, with some tendency to grouping, but in contrast with DH, no symmetry is present. Pruritus may be severe or entirely absent. Mucous membrane involvement is reported in 60% to 80% of patients ranging in severity from mild to severe oral or conjunctival lesions67; rarely mucosal involvement can be the sole clinical manifestation. LAD is “idiopathic” in most of the cases, and being an autoimmune disease itself, associations with other disorders of autoimmune and other origin are likely.5 There is a welldocumented association of LAD with inflammatory bowel disease (IBD), Crohn disease, and ulcerative colitis,68 as well as pancreatic lipase deficiency, chronic hepatitis,69 and even celiac disease (gluten-sensitive enteropathy),70 although by definition LAD is not associated with gluten enteropathy. Other associations of LAD include malignancies, which are to be found in about 5% of patients with LAD, presenting as both lymphoid and nonlymphoid malignant diseases. Several other triggers have been implicated in disease onset, including skin trauma,71 ultraviolet exposure, infections, and a wide range of drugs. The significance of these associations remains uncertain.

Dermatitis herpetiformis Dermatitis herpetiformis (DH), also known as Duhring’s disease, is an uncommon subepidermal blistering disease characterized by an intensely pruritic cutaneous eruption,

372 associated with a gluten-sensitive enteropathy. Several clinical and immunofluorescence features, typical for DH and not found in other immunobullous diseases, were identified that led to the current concept of DH as a distinct entity, strongly related to celiac disease in the spectrum of the gluten-sensitive diseases.72,73 Alternatively, it can be regarded as a skin manifestation of gluten sensitivity, a systemic disorder capable of affecting multiple organs. This notion is supported by demonstrated IgA autoantibodies in extraintestinal tissues such as the liver, muscle, and lymph nodes in patients with celiac disease.74 Similar IgA deposits were observed around the brain vessels in a patient with gluten ataxia.75,76 DH and celiac disease have a common immunogenetic background, sharing a strong association with certain major histocompatibility complex antigens, such as HLA-B8, HLA-DR3, and HLA-DQw2. First-degree relatives of patients with DH frequently experience development of celiac disease. Recently, it has been found that epidermal and tissue transglutaminases, cytosolic enzymes involved in cell envelope formation during keratinocyte differentiation, are the major autoantigens recognized in the skin lesions of DH and targeted by the circulating IgA antiendomysium (intermyofibril substance of smooth muscle) antibodies found in the serum of patients with DH and celiac disease.77 Clinically, DH presents with an intensely itchy polymorphic cutaneous eruption involving symmetrically the extensor surfaces, including elbows, knees, shoulders, sacrum, and buttocks. Morbidity is mainly related to the intense pruritus, scratching, discomfort, and insomnia, as well as to the risk for superimposed bacterial or viral infections. Systemic complications consist mainly of the symptoms of the associated gluten-sensitive enteropathy, which is now accepted to be present in practically all patients with DH, despite most of them having only subclinical gastrointestinal disease. Symptoms related to the gluten-sensitive enteropathy are milder than those seen in patients with celiac disease without skin findings, although up to 40% of children with DH have a history of chronic or relapsing diarrhea before the diagnosis of DH.78 Other clinical signs include malnutrition, weight loss, abdominal pain and dyspepsia, sometimes even mimicking peptic ulcer disease, and perforation. All patients with DH have evidence of gluten sensitivity in the small intestine, although only two thirds of them would show villous atrophy on a single biopsy. Patients with DH, similar to those with celiac disease, have a higher incidence of associated autoimmune conditions, especially thyroid problems, atrophic gastritis, type 1 diabetes, pernicious anemia, Addison disease, vitiligo, and various connective tissue disorders. Patients with DH, like patients with celiac disease, are at an increased risk for development of the so-called enteropathy-associated T-cell lymphomas.79 Once DH is diagnosed, examinations for possible signs and symptoms of such accompanying problems are necessary.80 DH and celiac disease have been described in association with such neurologic diseases as ataxia, dementia, and epilepsy. About 10% of patients with celiac disease experience

S. Vassileva et al. neurologic disorders.81 It has been postulated that the central and peripheral nervous systems are susceptible to immunemediated damage caused by gluten, although no convincing evidence for immune-mediated neurologic injury in DH has been confirmed.82 A study of 305 patients in Finland found no significant association between DH and neurologic disease.83 A cohort of 35 patients with DH had low prevalence of neurologic abnormalities, but the unexpected presence of a novel antispinal antibody was found in more than 50% of these patients, requiring further investigation.82

Epidermolysis bullosa acquisita Epidermolysis bullosa acquisita (EBA) is a rare subepidermal blistering disease, characterized by chronic course, resistance to therapy, and often debilitating sequelae. It is mediated by autoantibodies against type VII collagen of the BMZ in stratified squamous epithelia. Recently, type VII collagen was also found in the BMZ of the colon and in the intestinal epithelium.84 The two main clinical presentations of EBA include the mechanobullous or “classical” and the inflammatory phenotype. Classical EBA shows features reminiscent of hereditary dystrophic epidermolysis bullosa, with skin fragility, blisters, scarring, and milia formation limited to the trauma-prone skin surfaces. Alternatively, the inflammatory phenotype manifests with a widespread inflammatory blistering eruption similar to BP or LAD. In a subset of patients with predominant mucous membrane involvement, the disease manifests with blisters and scarring in the oral, ocular, vaginal, and other mucous membranes, leading to significant dysfunction, such as visual function loss, dysphagia, malnutrition, or even death. This clinical phenotype is indistinguishable from MMP. Similar to other immunobullous disorders, EBA has been related to a number of systemic diseases, including autoimmune disorders, malignancies, hematologic, infectious, and endocrine conditions.5 IBD, in particular, Crohn disease and less often, ulcerative colitis, seems to be most frequently associated with EBA to an extent that EBA is currently recognized as one of the extraintestinal manifestations of IBD. Crohn disease has been described in up to 30% of patients with EBA, although many of these observations were made before modern diagnostic criteria for EBA had been established. A recently published review of all previously described cases of EBA and IBD identified 42 reports of coexistence of both diseases in the literature: 35 cases of Crohn disease and 7 with ulcerative colitis.85 In the majority of cases, the onset of the gastrointestinal symptoms preceded or occurred simultaneously with the skin blistering disease. It has been hypothesized that chronic, but occasionally subclinical, inflammation of the gut can precede the development of EBA in all patients.86 The pathogenesis of IBD is not yet completely understood, but it has been proposed that autoimmune mechanisms

AIBDs as systemic diseases may also be responsible. It has been demonstrated that up to 68% of patients with Crohn disease have circulating antibodies against type VII collagen. 87 Anti-type VII collagen antibodies have been detected in patients with ulcerative colitis as well, although with a lower frequency than for Crohn disease. Apart from antibodies to type VII collagen, a number of other autoantibodies to different targets, including intestinal epithelial antigens, pancreatic proteins, cardiolipin, cytoskeletal proteins, Saccharomyces cerevisiae, and tropomyosin, as well as peripheral antineutrophil cytoplasmic antibodies, have been described in patients with IBD, but there is still no evidence for their direct pathogenic role. The exact significance of autoimmunity to type VII collagen in IBD pathogenesis and its relationship to EBA is not yet clarified. It has been proposed that autoimmunity to type VII collagen, which exists in both gut and skin, may explain why patients with EBA frequently have IBD. The presence of type VII collagen antibodies in patients with Crohn disease may be an epitope spreading phenomenon whereby inflammation originally invoked by Crohn disease could perturb the intestinal epithelial BMZ and cause alteration of BMZ components resulting in an ongoing autoimmunity to type VII collagen.87 Another possibility is that the epitopes of type VII collagen targeted by autoantibodies in EBA and IBD may differ, which could further explain the presence of EBA in some patients and the absence of skin blistering in the majority of patients with IBD. Based on all these data, a classification of EBA as manifestation (ie, involvement of the skin with blistering caused by primary IBD processes) or complication (skin blistering caused by secondary processes associated with IBD), including chronic inflammation or side effects of therapy of IBD, has been addressed; however, because production of blister-inducing autoantibodies against type VII collagen occurs only in some patients with IBD later in the course of their gastrointestinal disorder, the second possibility seems to be more likely.

Bullous systemic lupus erythematosus Another autoimmune blistering disease closely related to EBA and autoimmunity to type VII collagen is bullous systemic lupus erythematosus (BSLE). Over the years, BSLE has been recognized as a separate entity with distinct diagnostic criteria: (1) a diagnosis of systemic lupus erythematosus (SLE) by American Rheumatism Association criteria, (2) vesicles and bullae arising on but not limited to sun-exposed skin, (3) histopathology compatible with DH, (4) negative or positive IIF for BMZ autoantibodies, and (5) positive DIF at the BMZ.88 By definition, BSLE is a part of the clinical spectrum of SLE, a prototypic autoimmune disease with multisystem clinical manifestations in association with autoantibody production.

373 BSLE usually affects young adults in the second or third decade of life and is characterized by a rapid development of a widespread, symmetric, nonscarring vesiculobullous eruption showing predilection for the sun-exposed areas, but also for the chest, back, neck, and axillae.89 Depending on the predominance of inflammatory lesions and the distribution of the eruption, it may mimic BP, LAD, as well as both the inflammatory or “classical” variant of EBA.90 The onset and course of cutaneous lesions does not necessarily parallel the activity of the systemic involvement, but antinuclear antibody test results are generally positive. Other laboratory abnormalities related to SLE can include low levels of complement (C3, C4, CH50), anemia, leukopenia, thrombocytopenia, proteinuria or cellular casts on urinalysis, and an elevated erythrocyte sedimentation rate.91 An important clinical feature of BSLE that further differentiates it from EBA is its striking therapeutic response to dapsone. Systemic corticosteroids and immunosuppressors applied to control the visceral manifestations of SLE, in contrast, may be often ineffective to the eruption, and a combination of corticosteroids and dapsone is then indicated. Both BSLE and EBA have an increased incidence of HLA-DR2 haplotype that has been associated with hyperimmunity.92 It is possible that this genetic predisposition is responsible for an increased risk for development of autoimmunity to BMZ antigens. Overproduction of diverse autoantibodies by hyperreactive B cells as a result of depressed T suppressor activity is a protean feature of SLE. It has been hypothesized that antibodies to type VII collagen in BSLE are part of the autoantibody repertoire of SLE.93

Conclusions AIBDs are examples of a skin-specific autoimmune response, in which there are autoantibodies against adhesion molecules in the epidermis and the BMZ that are presumed to be pathogenic and to cause the blistering in the skin. Their diagnosis is based on the clinical findings, histology, and DIF and IIF, as well as identification of antigenic targets through other more specific and sensitive diagnostic laboratory methods. As soon as a distinct immunobullous disease is diagnosed, it is imperative to consider its potential systemic complications, as well as the potential autoimmune or inflammatory conditions that are frequently associated with it.

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